In alcoholism, relapse and neurodegeneration share a common molecular target, glutamate NM.D.A receptor (NM.D.AR) hyperactivity, which contributes to withdrawal, pathological conditioning and neurotoxicity. In consequence, inhibitory modulators of the NM.D.AR are both potential anti-relapse and neuroprotective agents. Agonists at the functionally similar alpha7-nicotinic acetylcholine receptors (nicAChRs) cause cross-desensitization of NM.D.ARs, and should therefore have similar therapeutic value. Few synthetic drugs with these specific pharmacological actions are yet available, but the presence of homologous receptors in insect CNS suggests that plants may have evolved metabolites with appropriate pharmacology as insect defenses. As part of a phase 1 STTR, we applied a differential high throughput screening approach to more than 1000 native plant species to identify those containing putative novel compounds with the required pharmacology. Candidate species have now been prioritized for further investigation including 2 with inhibitory NM.D.AR activity, 3 with alpha7-selective nicAChR agonist activity, and 3 with both types of activity. Extract fractions from representative species inhibit NM.D.A toxicity during alcohol withdrawal in a neuroblastoma screen. None of the species have been investigated for these actions before, and chemical analysis suggests that activity resides in compounds not previously known. This phase 2 STTR aims to (a) begin genomic optimization of active plant species using proprietary technology (b) separate relatively pure active compounds, and tentatively identify these (c) test semi-purified active compounds rigorously in screens and models relevant to relapse and neurodegeneration. In phase 3, the aim is to commercialize genomically-optimized plant species, and the best drug, or lead compound candidates in partnership with a strategic partner, Yaupon Pharmaceuticals. This project combines Naprogenix Incs novel plant biotechnology methods with the chemical analytical expertise and screening methods developed at the University of Kentucky. Because active compounds may be useful in many neurodegenerative conditions, their potential commercial value extends far beyond alcoholism. Support for this phase 2 STTR will ensure that this use will be investigated first.